Effects of Mechanical Stress and Carvedilol in Lamin A/C–Deficient Dilated Cardiomyopathy

Abstract

Rationale: Mutations in the LMNA gene, which encodes the nuclear lamina proteins lamin A and lamin C, are the most common cause of familial dilated cardiomyopathy (DCM). Mechanical stress-induced apoptosis has been proposed as the mechanism underpinning DCM in lamin A/C-deficient hearts, but supporting in vivo evidence has been lacking. Objective: Our aim was to study interventions to modify mechanical stress in heterozygous Lmna knockout (Lmna ؉/؊ ) mice. Methods and Results: Cardiac structure and function were evaluated before and after exercise training, thoracic aortic constriction, and carvedilol treatment. Lmna ؉/؊ mice develop adult-onset DCM with relatively more severe disease in males. Lmna ؉/؊ cardiomyocytes show altered nuclear morphology and perinuclear desmin organization, with enhanced responses to hypo-osmotic stress indicative of cytoskeletal instability. Despite these structural defects that provide a template for mechanical stress-induced damage, young Lmna ؉/؊ mice subjected to 6 weeks of moderate or strenuous exercise training did not show induction of apoptosis or accelerated DCM. In contrast, regular moderate exercise attenuated DCM development in male Lmna ؉/؊ mice. Sustained pressure overload generated by thoracic aortic constriction depressed ventricular contraction in young wild-type and Lmna ؉/؊ mice with no sex or genotype differences in the time-course or severity of response. Treatment of male Lmna ؉/؊ mice from 12 to 40 weeks with the ␤-blocker, carvedilol, prevented the dilatation and contractile dysfunction that was observed in placebo-treated mice. Conclusions: These data suggest that factors other than mechanical stress-induced apoptosis contribute to DCM and provide the first demonstration that regular moderate exercise and carvedilol can modify disease progression in lamin A/C-deficient hearts. (Circ Res. 2010;106:573-582.)Key Words: familial dilated cardiomyopathy Ⅲ lamin A/C Ⅲ mechanical stress Ⅲ exercise Ⅲ carvedilol M utations in the LMNA gene that encodes the nuclear lamina proteins lamin A and lamin C are the most common cause of familial dilated cardiomyopathy (DCM) identified to date, 1 accounting for 5% to 10% familial DCM overall and 30% to 45% families with DCM and conduction system disease (CD). [2][3][4][5] Affected individuals frequently have a rapidly progressive downhill clinical course, requiring pacemaker implantation or heart transplantation, with an increased risk of sudden death. [2][3][4][5] Despite the clinical importance of LMNA mutations, very little is known about mechanisms of disease pathogenesis and strategies to prevent DCM have not been investigated.Because one-third of DCM-causing LMNA mutations are stop codons, splice site variants or insertions/deletions that reduce lamin A/C protein levels, 1,5 Lmna knockout mice are a useful and clinically relevant model to study DCM mechanisms. 6 We have previously reported that homozygous Lmna knockout (Lmna Ϫ/Ϫ ) mice exhibit severe DCM by 4 to 6 weeks. 7 Heterozygous Lmna knockout (Lmna ϩ/Ϫ ) mice show ...

A Randomised, Placebo-controlled Trial of Carvedilol in Early Familial Dilated Cardiomyopathy

“…The recently reported finding that treatment with carvedilol from 12 weeks of age prevented the development of DCM in a murine model of inherited DCM [10] adds further weight to the argument for early use of ␤ blockers in EDCM and in particular for carvedilol. In comparison with other ␤-blocking drugs that selectively inhibit ␤1-adrenergic receptors, carvedilol blocks ␤1-, ␤2-and ␣1-adrenergic receptors and has a broader spectrum of action, including potent vasodilation, and anti-ischemic, anti-oxidant, anti-proliferative and antiapoptotic effects [21].…”

The Role of the Nuclear Lamina in Cancer and Apoptosis

“…Yet, studies in laminopathy animal models resulted in confl icting results. Heterozygous lmna +/− mice subjected to 6 weeks of moderate or strenuous exercise training did not show induction of apoptosis and even seemed to protect these mice from developing symptoms refl ective of laminopathy diseases [ 63 ]. In contrast, Lu et al [ 64 ] found a dramatic increase in frequency of apoptosis in the heart of transgenic mice with a human LMNA E82K mutation.…”

Genetics and Disease of Ventricular Muscle

“…Various therapies directed toward reversing biological processes downstream from the initiating genetic trigger have been shown to be effective in murine cardiomyopathy models, and some of these have been evaluated subsequently in human clinical trials. Examples of this include treatment with L-type calcium channel inhibitors, HMG CoA reductase inhibitors, antioxidants in HCM models, and bblockers and extracellular signal-regulated kinase (ERK) inhibitors in DCM models (Patel et al 2001;Semsarian et al 2002;Lombardi et al 2009;Muchir et al 2009;Chandar et al 2010;Yeoh et al 2011). Other new approaches to therapy that are currently under investigation include reversal of microRNA effects with antagomirs, and stem-cell therapies.…”